WO 2007/084786 (priority date: Jan. 20, 2006) describes certain pyrimidine derivatives having phosphatidylinositol 3-kinase (hereinafter referred to as “PI3K”) inhibiting properties, their use as pharmaceuticals and manufacturing processes thereof. One pyrimidine derivative disclosed in WO 2007/084786 is the selective phosphatidylinositol 3-kinase inhibitor compound 5-(2,6-Di-4-morpholinyl-4-pyrimidinyl)-4-trifluoromethylpyridin-2-amine, hereinafter referred to as “Compound A” or “the compound of formula A”.

Compound A is described in WO 2007/084786 in free form and as the hydrochloric acid salt. The manufacturing process for preparing Compound A is described in Example 10 of this document. The manufacturing processes described therein are, although suitable for small scale production, regarded as disadvantageous for commercial production.
WO International Patent Application PCT/US2011/053808 discloses a process for manufacturing pyrimidine compounds, including Compound A, and their corresponding salts and polymorphs. The process of preparing compound A and the monohydrochloride salt is summarized in FIG. 1. The second step of the process that leads to the boronic acid or boronic ester is complicated, with yields ranging from 30-60%. The choice of the base required to react with the acidic proton of the amide is critical and requires 5 equivalents of lithium amide in addition to 2.5 equivalents of butyl lithium at low temperature for the the Li/Br exchange reaction. Additional complications arise from precipitation of the anion. Moreover the boronic acid is unstable at high pH (>9) and low pH (<1). The Suzuki coupling step is also complicated by the Pd catalyst required and removal of the Pd catalyst during work up. The salt forming step is also complicated, as addition of more than 1 equivalent of HCl results in formation of the monohydrochloride salt of 5-(2,6-Di-4-morpholinyl-4-pyrimidinyl)-4-trifluoromethylpyridin-2-amine along with amounts of the dihydrochloride salt of 5-(2,6-Di-4-morpholinyl-4-pyrimidinyl)-4-trifluoromethylpyridin-2-amine, the latter salt limiting the purity of the monohydrochloride salt.
There is a need for improved manufacturing methods of such compounds, especially where the purity of the intermediate compounds improve the purity of the active product ingredient, Compound A and its pharmaceutically acceptable salts. In particular there is a need to provide processes that fulfill one or more of the following criteria: scalable, safer; higher overall purity; higher yielding and more economical, as compared to the process disclosed.